Does the presence of connective tissue disease modify survival in patients with pulmonary fibrosis?

OBJECTIVES: Previous studies into the survival differences between individuals with idiopathic pulmonary fibrosis and those with connective tissue disease associated pulmonary fibrosis (CTD-PF) have yielded mixed results. The aim of this study is to compare the survival of individuals with CTD-PF to those with idiopathic pulmonary fibrosis clinical syndrome (IPF-CS) using data derived from The Health Improvement network, a large primary care database in the UK. METHODS: Incident cases of CTD-PF and IPF-CS between the years 2000-2009 were identified. Survival analysis was performed using Kaplan-Meier methods, stratified by type of connective tissue disease. Cox regression was then used to compare mortality rates between the groups, adjusting for age, gender and year of diagnosis. RESULTS: A total of 324 cases of CTD-PF and 2209 cases of IPF-CS were followed up over a mean period of 2.3 years. During this period, 113 (34.9%) cases of CTD-PF and 1073 (48.6%) cases of IPF-CS died. The mortality rates for cases with CTD-PF and IPF-CS were 123.6 per 1000 person years (95%CI: 102.8-148.9) and 229.8 per 1000 person years (95% CI: 216.4-244.0) respectively. After adjusting for age, sex and year of diagnosis, cases with CTD-PF had a better prognosis compared to those with IPF-CS (HR 0.76,95%CI: 0.62-0.92). CONCLUSION: The prognosis of individuals with CTD-PF appears to be significantly better than those with IPF-CS, but remains an important cause of death in patients with connective tissue disease, and requires more effective treatment options.

Mortality trends in asbestosis, extrinsic allergic alveolitis and sarcoidosis in England and Wales.

BACKGROUND: To ascertain the trends in mortality from Asbestosis, Extrinsic Allergic Alveolitis (EAA) and Sarcoidosis in England and Wales, we analysed mortality data from the Office of National Statistics. METHODS: We calculated age and stratum specific mortality rates between 1968 and 2008 and applied these to the 2008 population to generate annual standardised expected number of deaths. Poisson regression was used to calculate annual mortality rate ratios. RESULTS: From 1968 to 2008 there were 1958 registered deaths from Asbestosis, 878 deaths from EAA and 3544 deaths from Sarcoidosis. The Asbestosis mortality rate increased from 0.04 (95% CI 0.03-0.05) in the 1968-1972 calendar period to 0.12 (95% CI 0.10-0.13) in the 2005-2008 period whist the mortality from EAA increased marginally from 0.04 (95% CI 0.03-0.05) in the 1968-1972 calendar period to 0.08 (95% CI 0.07-0.09) in the 2005-2008 period. Mortality from Sarcoidosis increased by approximately 9% a year. DISCUSSION: Our findings show that the mortality from Asbestosis continues to rise in the UK. Overall mortality rates from EAA remained stable throughout the same period but it was higher in males and in older people. There was a slight increase in mortality from Sarcoidosis over the study period which was greater in women.

The rising incidence of idiopathic pulmonary fibrosis in the U.K.

BACKGROUND: Previous studies have shown that the incidence of idiopathic pulmonary fibrosis (IPF) is rising in the U.K. and U.S.A. Death registrations and primary care data were used to determine the current trends in IPF incidence in the U.K. Because routine clinical data sets were used, the term IPF clinical syndrome (IPF-CS) is used to describe individuals in this study. METHODS: Age- and stratum-specific death registration rates between 1968 and 2008 were calculated and these were applied to the 2008 population to generate annual standardised expected number of deaths. Annual mortality rate ratios were calculated using Poisson regression. Computerised primary care records were used to determine incidence rates of IPF-CS between 2000 and 2008 stratified by age, sex and geographical region, and survival rates between calendar periods were compared. RESULTS: Annual death certificate recording of IPF-CS rose sixfold across the study period from 0.92 per 100,000 in the 1968-1972 calendar periods to 5.10 per 100,000 in the 2006-2008 calendar period, and were higher in men and the older age groups. The incidence of IPF-CS in primary care increased by 35% from 2000 to 2008, with an overall incidence rate of 7.44 per 100,000 person-years (95% CI 7.12 to 7.77). Incidence was higher in men, the older population and in Northwest England. CONCLUSIONS: The incidence of IPF-CS in primary care and registered deaths from this cause in the U.K. continues to rise in the 21st century. The current findings suggest that there are >5000 new cases diagnosed each year in the U.K.

Effect of artesunate and mefloquine in combination on the Fridericia corrected QT intervals in Plasmodium falciparum infected adults from Thailand.

OBJECTIVE: To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. METHODS: We measured the Fridericia corrected QT (QTcF) intervals on 12 lead ECGs on days (D) 0, 3, 7 in Plasmodium falciparum infected adults, treated with oral artesunate (AS) and MQ as a new fixed dose (n = 25) combination or loose tablets (n = 25) over 3 days. Target total doses were 12 mg/kg of AS and 24-25 mg/kg of MQ. MQ concentrations ([MQ]) were measured by HPLC. RESULTS: All ECG intervals were similar between drug arms and were combined for analysis. Mean QTcF values were 389 (D0), 407 (D3) and 399 (D7) ms (Ps < 0.003 vs. D0); corresponding heart rates and [MQ]s were 83, 67 and 73 beats/minute (Ps ≤ 0.0003 vs. D0) and 0, 3095 and 1721 ng/ml. One male patient (loose arm) had a D3 QTcF 504 ms (D0 406 ms, D7 433 ms). In the modelling of QTcF and JTcF from D0 to D7, significant effects were observed individually for [MQ], temperature and heart rate (HR). The MQ AUC(0-∞) was not a significant factor. Using a manual descending, model building approach to select variables, the HR was the only significant variable (P = 0.001) over time in the model that best explained the changes in the QTcF and JTcF intervals. CONCLUSIONS: In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals.

New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase IIb safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine.

A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P < or = 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P < or = 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.

In vitro and in vivo evaluation of self-microemulsifying drug delivery system of buparvaquone.

AIM: The aim of this study was to prepare a lipid-based self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of a poorly water-soluble compound, buparvaquone (BPQ). METHODS: The solubility of BPQ was determined in various vehicles, and pseudo-ternary phase diagrams were constructed to determine the microemulsion region. A series of formulations with different compositions were selected in the microemulsion region for assessment of self-emulsification time and droplet size. The optimized SMEDDS formulation was used for in vitro dissolution and pharmacokinetic studies in rabbits. RESULTS: The optimum formulation of SMEDDS consisted of Capryol 90 (9.82%), Cremophor EL (70.72%), Labrasol (17.68%), and BPQ (1.78%). Emulsification time and the mean droplet size were found to be 1 minute and 18.0 +/- 0.25 nm, respectively, for the optimum formulation. The cumulative percentage of drug released in 90 minutes was 100% in both SGF and SIF. The calculated absolute oral bioavailability for BPQ was found to be 40.10%. CONCLUSIONS: The optimum SMEDDS formulation was increased the rate and extent of absorption of BPQ. The formulation is suitable for oral administration of BPQ. It would be useful to conduct efficacy studies of BPQ in diseased animal models and subsequently for toxicokinetics studies.

Chemical constituents and in vitro anticancer activity of Typhonium flagelliforme (Araceae).

AIM OF THE STUDY: Typhonium flagelliforme is an indigenous plant of Malaysia and is used by the local communities to treat cancer. This study aims to identify the chemical constituents of Typhonium flagelliforme particularly those which have antiproliferative properties towards human cancer cell lines. MATERIALS AND METHODS: Purification of the chemical constituents by various chromatographic procedures was guided by the antiproliferative activity. Identification of the chemical constituents was carried out by various spectroscopic techniques including high resolution MS and NMR. The antiproliferative activity was assayed using MTT on NCI-H23 (lung cancer) and HS578T (breast cancer) cell lines. Microscopic observation and DeadEnd colourimetric TUNEL assay was used to identify the apoptotic mode of cell death. RESULTS AND CONCLUSION: Four pheophorbide related compounds, namely pheophorbide-a, pheophorbide-a', pyropheophorbide-a and methyl pyropheophorbide-a were identified in the most active fraction, D/F19. These constituents exhibited antiproliferative activity against cancer cells and the activity increased following photoactivation. However, the greater antiproliferative activity exhibited by D/F19 itself compared to the pheophorbides and its other subfractions suggests some form of synergistic action between the constituents. The inhibitory effect of D/F19 and the pheophorbides was apoptotic in the absence of light. Other chemical constituents that have been identified in this study include hexadecanoic acid, oleic acid, linoleic acid, linolenic acid, campesterol, stigmasterol and beta-sitosterol. Most of the chemical constituents identified in this plant have not been reported previously.

Validation of high performance liquid chromatography-electrochemical detection methods with simultaneous extraction procedure for the determination of artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine in human plasma for application in clinical pharmacological studies of artesunate-amodiaquine drug combination.

With the expanded use of the combination of artesunate (AS) and amodiaquine (AQ) for the treatment of falciparum malaria and the abundance of products on the market, comes the need for rapid and reliable bioanalytical methods for the determination of the parent compounds and their metabolites. While the existing methods were developed for the determination of either AS or AQ in biological fluids, the current validated method allows simultaneous extraction and determination of AS and AQ in human plasma. Extraction is carried out on Supelclean LC-18 extraction cartridges where AS, its metabolite dihydroartemisinin (DHA) and the internal standard artemisinin (QHS) are separated from AQ, its metabolite desethylamodiaquine (DeAQ) and the internal standard, an isobutyl analogue of desethylamodiaquine (IB-DeAQ). AS, DHA and QHS are then analysed using Hypersil C4 column with acetonitrile-acetic acid (0.05M adjusted to pH 5.2 with 1.00M NaOH) (42:58, v/v) as mobile phase at flow rate 1.50ml/min. The analytes are detected with an electrochemical detector operating in the reductive mode. Chromatography of AQ, DeAQ and IB-DeAQ is carried out on an Inertsil C4 column with acetonitrile-KH(2)PO(4) (pH 4.0, 0.05M) (11:89, v/v) as mobile phase at flow rate 1.00ml/min. The analytes are detected by an electrochemical detector operating in the oxidative mode. The recoveries of AS, DHA, AQ and DeAQ vary between 79.1% and 104.0% over the concentration range of 50-1400ng/ml plasma. The accuracies of the determination of all the analytes are 96.8-103.9%, while the variation for within-day and day-to-day analysis are <15%. The lower limit of quantification for all the analytes is 20ng/ml and limit of detection is 8ng/ml. The method is sensitive, selective, accurate, reproducible and suited particularly for pharmacokinetic study of AS-AQ drug combination and can also be used to compare the bioavailability of different formulations, including a fixed-dose AS-AQ co-formulation.

Typhonium flagelliforme inhibits cancer cell growth in vitro and induces apoptosis: an evaluation by the bioactivity guided approach.

AIM OF THE STUDY: Typhonium flagelliforme (Lodd.) Blume (Araceae) is a Malaysian plant used locally to combat cancer. In order to evaluate its antiproliferative activity in vitro and to possibly identify the active chemical constituents, a bioactivity guided study was conducted on the extracts of this plant. MATERIALS AND METHODS: The active extracts of Typhonium flagelliforme were fractionated by flash column chromatography and each fraction was evaluated for antiproliferative activity using MTT assay. The apoptotic effect of the active fraction was determined microscopically and by using TUNEL colorimetric assay. GC-MS and NMR were used to determine the chemical constituents of this active fraction. RESULTS: Several fractions of the hexane and dichloromethane extracts were found to inhibit the growth of NCI-H23 non-small cell lung carcinoma cell line significantly, with IC(50)<15 microg/ml. However, most of these active fractions were also found to inhibit the growth of non-tumorigenic BALB/c 3T3 mouse fibroblast cell line except for fraction 21 of the dichloromethane extract (D/F21). This particular fraction was not only less cytotoxic to the non-tumorigenic cells, where the IC(50) was 48.6 microg/ml compared to IC(50) 7.5 microg/ml for NCI-H23, but it was also found to induce apoptosis in the cancer cell line. GC-MS analysis revealed that D/F21 contains hexadecanoic acid, 1-hexadecene, phytol and a derivative of phytol. The presence of non-saturated fatty acids in this fraction was confirmed by nuclear magnetic resonance spectroscopy. CONCLUSIONS: D/F21 was found to be the active and cancer cell line specific fraction of Typhonium flagelliforme. Its major chemical constituents had been determined spectroscopically.

The use of rapid assessment methodology to compliment existing national assessment and surveillance data: a study among injecting drug users in Penang, Malaysia.

The study explores how data collated from rapid assessment can enhance those produced by national level surveillance systems, in this case the national drug information (NADI) system in Malaysia. Qualitative data were collected in keeping with internationally accepted guidance on rapid assessment methods in the field of substance use. An inductive research strategy was employed. The rapid assessment produced multiple data on local drug use practices and how these were influenced by the contexts of use. The assessment points to the importance of collecting data not only on patterns of drug use but also on the health and social consequences of drug use. We suggest that the current national drug information system places greater emphasis on behavioural and health-related variables in order to better understand the potential relationships between drug use and health-related risk, including HIV/AIDS.

Optimization and validation of RP-HPLC-UV method with solid-phase extraction for determination of buparvaquone in human and rabbit plasma: application to pharmacokinetic study.

A simple, sensitive and specific reversed-phase high-performance liquid chromatographic method with UV detection at 251 nm was developed for quantitation of buparvaquone (BPQ) in human and rabbit plasma. The method utilizes 250 microL of plasma and sample preparation involves protein precipitation followed by solid-phase extraction. The method was validated on a C18 column with mobile phase consisting of ammonium acetate buffer (0.02 m, pH 3.0) and acetonitrile in the ratio of 18:82 (v/v) at a flow rate of 1.1 mL/min. The calibration curves were linear (correlation coefficient>or=0.998) in the selected range. The method is specific and sensitive with limit of quantitation of 50 ng/mL for BPQ. The validated method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions and BPQ was found to be stable. Partial validation studies were carried out using rabbit plasma and intra- and inter-day precision and accuracy were within 7%. This method is simple, reliable and can be routinely used for preclinical pharmacokinetic studies for BPQ.

An analytical method with a single extraction procedure and two separate high performance liquid chromatographic systems for the determination of artesunate, dihydroartemisinin and mefloquine in human plasma for application in clinical pharmacological studies of the drug combination.

The combination of two sensitive, selective and reproducible reversed phase liquid chromatographic (RP-HPLC) methods was developed for the determination of artesunate (AS), its active metabolite dihydroartemisinin (DHA) and mefloquine (MQ) in human plasma. Solid phase extraction (SPE) of the plasma samples was carried out on Supelclean LC-18 extraction cartridges. Chromatographic separation of AS, DHA and the internal standard, artemisinin (QHS) was obtained on a Hypersil C4 column with mobile phase consisting of acetonitrile-0.05 M acetic acid adjusted to pH 5.2 with 1.0M NaOH (42:58, v/v) at the flow rate of 1.50 ml/min. The analytes were detected using an electrochemical detector operating in the reductive mode. Chromatography of MQ and the internal standard, chlorpromazine hydrochloride (CPM) was carried out on an Inertsil C8-3 column using methanol-acetonitrile-0.05 M potassium dihydrogen phosphate adjusted to pH 3.9 with 0.5% orthophosphoric acid (50:8:42, v/v/v) at a flow rate of 1.00 ml/min with ultraviolet detection at 284 nm. The mean recoveries of AS and DHA over a concentration range of 30-750 ng/0.5 ml plasma and MQ over a concentration of 75-1500 ng/0.5 ml plasma were above 80% and the accuracy ranged from 91.1 to 103.5%. The within-day coefficients of variation were 1.0-1.4% for AS, 0.4-3.4% for DHA and 0.7-1.5% for MQ. The day-to-day coefficients of variation were 1.3-7.6%, 1.8-7.8% and 2.0-3.4%, respectively. Both the lower limit of quantifications for AS and DHA were at 10 ng/0.5 ml and the lower limit of quantification for MQ was at 25 ng/0.5 ml. The limit of detections were 4 ng/0.5 ml for AS and DHA and 15 ng/0.5 ml for MQ. The method was found to be suitable for use in clinical pharmacological studies.

Permeability of atenolol and propranolol in the presence of dimethyl sulfoxide in rat single-pass intestinal perfusion assay with liquid chromatography/UV detection.

A simple and sensitive RP-HPLC-UV method was developed and validated for simultaneous determination of atenolol and propranolol and subsequently applied to investigate the effect of dimethyl sulfoxide in rat in situ intestinal permeability studies. Atenolol (400 microm) and propranolol (100 microm) were perfused in the small intestine of anaesthetized (pentobarbitone sodium 60 mg/kg, i.p.) male Sprague-Dawley rats either in the presence (1, 3 and 5%) or in the absence of dimethyl sulfoxide. There was no significant alteration (p > 0.05) in the permeability of atenolol and propranolol, which indicated there was no effect of various concentrations of dimethyl sulfoxide (1-5%) on the membrane integrity of the rat intestinal tissues. The analytical method was validated on a C(4) column with a mobile phase comprising ammonium acetate buffer (pH 3.5, 0.02 m) and acetonitrile in the ratio of 30:70 (v/v) at a flow rate of 1.0 mL/min. The validated method was found to be accurate and precise and stability studies were carried out at different storage conditions and both analytes were found to be stable. These findings are applicable for determining the absorbability of water-insoluble drugs and new chemical entities for the purpose of classifying them in the biopharmaceutical classification system.

Development and validation of RP-HPLC-UV method for simultaneous determination of buparvaquone, atenolol, propranolol, quinidine and verapamil: a tool for the standardization of rat in situ intestinal permeability studies.

A simple, sensitive and specific reversed phase high performance liquid chromatographic (RP-HPLC) method with UV detection at 251 nm was developed for simultaneous quantitation of buparvaquone (BPQ), atenolol, propranolol, quinidine and verapamil. The method was applicable in rat in situ intestinal permeability study to assess intestinal permeability of BPQ, a promising lead compound for Leishmania donovani infections. The method was validated on a C-4 column with mobile phase comprising ammonium acetate buffer (0.02 M, pH 3.5) and acetonitrile in the ratio of 30:70 (v/v) at a flow rate of 1.0 ml/min. The retention times for atenolol, quinidine, propranolol, verapamil and BPQ were 4.30, 5.96, 6.55, 7.98 and 8.54 min, respectively. The calibration curves were linear (correlation coefficient > or =0.996) in the selected range of each analyte. The method is specific and sensitive with limit of quantitation of 15 microg/ml for atenolol, 0.8 microg/ml for quinidine, 5 microg/ml for propranolol, 10 microg/ml for verapamil and 200 ng/ml for BPQ. The validated method was found to be accurate and precise in the working calibration range. Stability studies were carried out at different storage conditions and all the analytes were found to be stable. This method is simple, reliable and can be routinely used for accurate permeability characterization.

A new and simple solid-phase extraction method for LC determination of pyronaridine in human plasma.

A new approach using a simple solid-phase extraction technique has been developed for the determination of pyronaridine (PND), an antimalarial drug, in human plasma. After extraction with C18 solid-phase sorbent, PND was analyzed using a reverse phase chromatographic method with fluorescence detection (at lambda(ex)=267 nm and lambda(em)=443 nm). The mean extraction recovery for PND was 95.2%. The coefficient of variation for intra-assay precision, inter-assay precision and accuracy was less than 10%. The quantification limit with fluorescence detection was 0.010 microg/mL plasma. The method described herein has several advantages over other published methods since it is easy to perform and rapid. It also permits reducing both, solvent use and sample preparation time. The method has been used successfully to assay plasma samples from clinical pharmacokinetic studies.

Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria.

We report the first detailed pharmacokinetic assessment of intrarectal (i.r.) artesunate (ARS) in African children. Artesunate was given intravenously (i.v.; 2.4 mg/kg of body weight) and i.r. (10 or 20 mg/kg formulated as 50- or 200-mg suppositories [Rectocaps]) in a crossover study design to 34 Ghanaian children with moderate falciparum malaria. The median relative bioavailability of dihydroartemisinin (DHA), the active antimalarial metabolite of ARS, was higher in the low-dose i.r. group (10 mg/kg) than in the high-dose i.r. group (20 mg/kg) (58 versus 23%; P = 0.018). There was wide interpatient variation in the area under the concentration-time curve after i.r. ARS administration (up to 9-fold in the high-dose group and 20-fold in the low-dose group). i.r. administered ARS was more rapidly absorbed in the low-dose group than the high-dose group (median [range] absorption half-lives, 0.7 h [0.3 to 1.24 h] versus 1.1 h [0.6 to 2.7 h] [P = 0.023]. i.r. administered ARS was eliminated with a median (range) half-life of 0.8 h (0.4 to 2.7 h) (low-dose group and 0.9 h (0.1 to 2.5 h) (high-dose group) (P = 1). The fractional clearances of DHA were 3.9, 2.6, and 1.5 liters/kg/h for the 20-mg/kg, 10-mg/kg and i.v. groups, respectively (P = 0.001 and P = 0.06 for the high-and low-dose i.r. groups compared with the i.v. groups, respectively). The median volumes of distribution for DHA were 1.5 liters kg (20 mg/kg, i.r. group), 1.8 liters/kg (10 mg/kg, i.r. group), and 0.6 liters/kg (i.v. group) (P < 0.05 for both i.r. groups compared with the i.v. group). Parasite clearance kinetics were comparable in all treatment groups. i.r. administered ARS may be a useful alternative to parenterally administered ARS in the management of moderate childhood malaria and should be studied further.

Pharmacokinetics of artesunate after single oral administration to rats.

BACKGROUND: Artesunate is a commonly used antimalarial drug derived from artemisinin. It is rapidly converted to dihydroartemisinin. Little is known on this conversion in the GI tract and blood, and how this influences absorption. In order to study the absorption phase of the kinetics of artesunate following oral administration in rats, samples were collected at baseline, and then 0.5, 2, 5, 10, 15, 30, 45, 60 and 120 minutes after a single dose of 150 mg. RESULTS: Peak concentration of parent artesunate and dihydroartemisinin was achieved within 5 and 37.5 +/- 8.7 min, respectively of start of administration through gavage. The half lives of absorption were 2.73 +/- 0.85 and 12.49 +/- 2.49 min, respectively. CONCLUSIONS: These times were considerably shorter for artesunate than those found in studies which start sampling later. The profiles of parent compound and metabolite result from a complex equation dictated by the pH-dependent rates of hydroxylation of artesunate to dihydroartemisinin, the different rates at which either compounds are absorbed, and the catalytic hydroxylation by esterases. The rate of chemical oxidation of artesunate is pH dependent; this explains its rapid conversion to dihydroartemisinin in the stomach, as compared to its greater stability in other compartments at higher pH and in plasma. We propose that variable proportions of absorption take place in the stomach, and conclude that parent artesunate reaches an early peak within minutes of dosing, and that the early dihydroartemisinin levels result primarily from the absorption of the metabolite as such.

Pharmacokinetics of artemisinin-type compounds.

Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.

Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria.

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < or = 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunate-associated antimalarial activity.